The Massachusetts Alzheimer's Disease Research Center, established in 1984, proposes to continue and expand its research into the underpinnings of Alzheimer's and related dementias with 5 major goals. First, we will focus on the earliest stages of the disease process, when symptoms and signs are subtle, or even undetectable, by bringing to bear an integrated multidisciplinary team of clinicians and scientists. Second, we will continue to provide critical infrastructure and resources to support Alzheimer disease and dementia related research across a range of institutions including Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, and the Harvard School of Public Health as well as supporting national initiatives. Third, we will innovate with technical developmental projects in each Core, targeting the boundaries of cognitive ageing and disease. Fourth, we are committed to mentoring, educating, and developing future leaders through formal training or mentoring programs in each Core. Fifth, we continue to reach out to the surrounding community in order to communicate the urgency of understanding this devastating disease, and to enhance recruitment of a diverse pool of subjects and patients for critical studies. These broad aims are distributed among the mandated Administration, Clinical, Data Management and Statistics, Neuropathology and Outreach Cores, along with a new Neuroimaging Core. Each Core provides support for, and helps catalyze, the MADRC's mission, including active participation in national programs (e.g. NACC, ADNI, ADCS, ADGC, DIAN), more than 40 local clinical initiatives, and pilot projects. Three small R01 style projects leverage these Cores and are designed to marry cutting edge science with the clinical programs. Project 1, led by a new junior investigator, Dr Hedden, uses state-of-the art fMRI and Connectome techniques (a new technology that illuminates white matter pathways) as well as quantitative structural MRI approaches to study the neural system basis of the earliest cognitive impairments. Project 2, led by Dr Gomez-Isla (a senior investigator recruited to our Center in the current grant period) combines resources with 5 other ADCs to define the neuropathological phenotype of individuals who are amyloid imaging-positive and cognitively normal. Project 3, led by Dr Hyman, explores a new transgenic mouse model of Alzheimer disease that develops tangles in entorhinal cortex and widespread plaques and compares it to human neuropathological samples - to examine experimentally the neural system biology of this early point in the disease process. Together these efforts are aimed at targeting early disease phenotypes - as national efforts towards early intervention and prevention strategies unfold. Along with parallel ongoing multidisciplinary studies of established dementias, we believe the MADRC has made, and is well positioned to continue to make, strong contributions to Alzheimer research.